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Dev Cell. 2016 Nov 21;39(4):466-479. doi: 10.1016/j.devcel.2016.09.005. Epub 2016 Oct 6.

Acetylation of VGLL4 Regulates Hippo-YAP Signaling and Postnatal Cardiac Growth.

Author information

1
Department of Cardiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA. Electronic address: zlin@enders.tch.harvard.edu.
2
Department of Cardiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
3
Department of Cardiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA; Peking University, Fifth School of Clinical Medicine, Beijing 100730, China.
4
Department of Cardiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
5
Rowland Institute at Harvard, Harvard University, Cambridge, MA 02142, USA.
6
Department of Cardiology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
7
Department of Anatomy & Histology, Bosch Institute, University of Sydney, Sydney, NSW 2006, Australia.
8
Institute of Molecular Medicine, Peking University, PKU-Tsinghua U Joint Center for Life Sciences, Beijing 100871, China.
9
Department of Cardiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA. Electronic address: wpu@pulab.org.

Abstract

Binding of the transcriptional co-activator YAP with the transcription factor TEAD stimulates growth of the heart and other organs. YAP overexpression potently stimulates fetal cardiomyocyte (CM) proliferation, but YAP's mitogenic potency declines postnatally. While investigating factors that limit YAP's postnatal mitogenic activity, we found that the CM-enriched TEAD1 binding protein VGLL4 inhibits CM proliferation by inhibiting TEAD1-YAP interaction and by targeting TEAD1 for degradation. Importantly, VGLL4 acetylation at lysine 225 negatively regulated its binding to TEAD1. This developmentally regulated acetylation event critically governs postnatal heart growth, since overexpression of an acetylation-refractory VGLL4 mutant enhanced TEAD1 degradation, limited neonatal CM proliferation, and caused CM necrosis. Our study defines an acetylation-mediated, VGLL4-dependent switch that regulates TEAD stability and YAP-TEAD activity. These insights may improve targeted modulation of TEAD-YAP activity in applications from cardiac regeneration to cancer.

KEYWORDS:

Hippo-YAP pathway; TEAD1; VGLL4; acetylation; cardiac; cardiomyocyte; degradation; necrosis; proliferation

PMID:
27720608
PMCID:
PMC5121000
DOI:
10.1016/j.devcel.2016.09.005
[Indexed for MEDLINE]
Free PMC Article

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